Pancreatic adenocarcinoma, the tenth most common human cancer, grows extremely rapidly, disseminates early and occult metastases are frequent. Non invasive staging modalities have shown limited ability to detect local invasion or small volume metastatic disease. 18F-labeled 2-deoxy-2-fluoro-D-glucose (18F-FDG), which has greatly improved the diagnosis and staging of numerous tumors, does not significantly increase the accuracy of preoperative determination of resectability of pancreatic adenocarcinoma. Therefore, a non invasive method to improve preoperative staging would be extremely useful.
Indisputable success of scintigraphy and radiotherapy of neuroendocrine tumors has been obtained with somatostatin analogues labeled with radiometals, such as 111In, 68Ga, 90Y or 177Lu. PET imaging with 68Ga potentially provides higher diagnostic efficacy than SPECT. Therapy with 90Y or 177Lu affords symptomatic improvement, prolonged survival and better quality of life in some instances. However, somatostatin analogs only bind tumors that express somatostatin receptors.
It has been shown that 75-88% ductal pancreatic adenocarcinoma express neurotensin (NT) receptors, but little or no somatostatin receptors. NT receptors have been proposed as new markers for this tumor since they were not detected in normal pancreas and chronic pancreatitis. NT receptors were also identified in other tumor cells as, for example, Ewing's sarcoma, meningiomas, small cell lung carcinoma and colon adenocarcinoma. In patients with invasive ductal breast cancers, 91% of tumors are positive for the neurotensin high-affinity receptor (NTSR1), while it is poorly expressed or absent in normal cells (Souaze et al., Cancer Res. (2006) 66, 6243-6249). This recent work points out the diagnostic and therapeutic potential of molecules targeting NTSR1 receptor.
Neurotensin, the natural ligand for neurotensin receptors, is a thirteen amino acid peptide, isolated from bovine hypothalamus and has the following structure: pGlu-Leu-Tyr-Glu-Asn-Lys-Pro-Arg-Arg-Pro-Tyr-Ile-Leu-OH.
Examples of neurotensin analogues bearing a chelating moiety suitable for labeling with technetium or rhenium may be found in the literature, e.g. Garcia-Garayoa et al., Eur J Nucl Med Mol Imaging, (2009) 36(1), p. 37-47).
Acyclic or macrocylic poly(aminocarboxylate) compounds are suitable chelators for radioisotopes such as 111In, 67Ga, 68Ga, 90Y, 86Y, 177Lu, 212Bi, 213Bi, 64Cu, 67Cu, 44Sc, 44mSc, 47Sc. To target NTSR1 positive tumors, neurotensin ligands bearing acyclic or macrocyclic poly(aminocarboxylate) chelators such as DTPA or DOTA have thus been developed (de Visser et al., Eur. J. Nucl. Med. Mol. Imaging. (2003), 30, 1134-1139; Janssen et al., Cancer Biother Radiopharm. (2007), 22(3), 374-381; Hillairet de Boisferon et al., Bioconjug. Chem. (2002), 13, 654-662).
The efficiency of a compound targeting neurotensin receptor-positive tumors may be quantified by several criteria:                tumor uptake must be as high as possible, to allow their good detection or treatment;        tumor to normal tissue uptake ratios must be as high as possible, to achieve good contrasts in imaging and to minimize the irradiation of normal tissue during treatment.        
If some technetium or rhenium-labeled neurotensin analogues may be considered as reasonably good according to these criteria, neurotensin analogues bearing acyclic or macrocyclic poly(aminocarboxylate) chelating agent, such as DTPA, DOTA or one of their derivatives, described so far have shown lower tumor uptake, higher kidney accumulation or both.
Here is provided new poly(aminocarboxylate) neurotensin analogues providing higher tumor uptake and/or higher tumor to normal tissue uptake ratios, particularly higher tumor to kidneys uptake ratio, than poly(aminocarboxylate) neurotensin analogues previously described in the literature. This is particularly important at early time points after activity injection (preferably before 24 hours post-injection), so that:                high contrast images may be recorded before radioactive decay of the radionuclide reduces imaging sensitivity, and        exposure of normal tissues—which is also maximum at early time points is reduced.        